Catalytic halogenation of activated methylene and methine compounds

Abstract

A process for the halogenation of activated methylene and methine compounds with at least equimolar amounts of an electrophilic halogenation reagent, which comprises reacting said activated methylene and methine compounds in the presence of catalytic amounts of a titanium compound of the formula I or of a titanium compound of the formula II R 1 TiX 1 X 2 X 3   (I), R 2 R 3 TiX 1 X 2   (II), in which R 1 is chlorine, bromine or iodine, a substituted or unsubstituted cyclopentadienyl or indenyl, and X 1 , X 2 and X 3 are, independently of one another, chlorine, bromine or iodine, or X 1 , X 2 and X 3 are an organic sulfonate group where R 1 is a substituted or unsubstituted cyclopentadienyl or indenyl; R 2 and R 3 are a substituted or unsubstituted cyclopentadienyl or indenyl, R 2 and R 3 together are a substituted or unsubstituted and bridged or unbridged biscyclopentadienyl or bisindenyl, or R 2 and R 3 together are a substituted or unsubstituted 1,3-, 1,4- or 1,5-diolate, and X 1 , and X 2 are, independently of one another, chlorine, bromine or iodine or an organic sulfonate group. If the diolate is enantiopure, the process is enantioselective on use of racemic activated methine compounds.

What is claimed is:  
     
       1. A process for halogenation of an activated methylene or methine compound with at least equimolar amounts of an electrophilic halogenation reagent, which comprises reacting said activated methylene or methine compound with said electrophilic halogenation reagent in the presence of a catalytic amount of a titanium compound of the formula I or of a titanium compound of the formula II 
       
         
           R 1 TiX 1 X 2 X 3   (I),  
         
       
       
         
           R 2 R 3 TiX 1 X 2   (II),  
         
       
       in which 
       R 1  is chlorine, bromine or iodine, a substituted or unsubstituted cyclopentadienyl or indenyl, and X 1 , X 2  and X 3  are, independently of one another, chlorine, bromine or iodine, or X 1 , X 2  and X 3  are an organic sulfonate group where R 1  is a substituted or unsubstituted cyclopemtadienyl or indenyl; R 2  and R 3  are a substituted or unsubtitued cyclopentadienyl or indenyl, R 2  and R 3  together are a substituted or unsubstituted and bridged or unbridged biscyclopentadienyl or bisindenyl, or R 2  and R 3  together are a substituted or unsubstituted 1,3-, 1,4- or 1,5-diolate, and X 1  and X 2  are, independently of one another, chlorine, bromine or iodine or an organic sulfonate group.  
     
     
       2. The process according to  claim 1 , wherein the activated methylene or methine compound is a saturated or unsaturated aliphatic, cycloaliphatic, heteroaliphatic or heterocycloaliphatic compound having a hetero atom selected from the group of O, S and N and containing 2 to 30 C atoms, no system or aromatic or heteroaromatic system or both aromatic and heteroaromatic systems being fused to the ring of the cyclic compound, and the compound being unsubstituted or substituted by —CN, —NH 2 , C 1 -C 18 alkyl, C 1 -C 18 alkoxy, C 1 -C 8 haloalkyl, —NH(C 1 -C 12 alkyl), —(C 1 -C 12 alkyl) 2 , —SO 3 M, —COOM, —COOH, —COOC 1 -C 20 alkyl or -phenyl or benzyl or -diphenylmenthyl,  CO—NH 2 , —CO—NH(C 1 -C 12 alkyl), —CO—N(C 1 -C 12 alkyl) 2 , C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkoxy, C 5 -C 12 heterocycloalkyl or C 5 -C 12 heterocycloalkoxy having 1 to 3 hetero atoms selected from the group of O, S and N, C 6 -C 12 aryl or C 6 -C 12 aryloxy, C 4 -C 11 heteroaryl or C 4 -C 11 heteroaryloxy having 1 to 3 hetero atoms selected from the group of O, S and N, C 7 -C 12 aralkyl or C 5 -C 12 heteroalkyl having 1 to 3hetero atoms selected from the group of O, S and N, where M is Li, Na or K, and cyclic substitutents in turn being unsubstituted or substituted by halogen, —CN, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 1 -C 8 alkoxy or other aforementioned substituents. 
     
     
       3. The process according to  claim 2 , wherein the activated methylene and methine compounds are those of the formulae III and IV, 
       
         
           NC—CH(R 4 )—CN  (III),  
         
       
       
         
           R 5 —CH(R 4 )—C(═O)‥R 6   (IV),  
         
       
       in which R 4  is hydrogen, linear or branched C 1 -C 18 alkyl, C 2 -C 18 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkyl-C 1 -C 6 alkyl, C 3 -C 12 cycloalkenyl-C 1 -C 6 alkyl, C 6 -C 18 aryl, C 7 -C 18 aralkyl, C 8 -C 18 aralkenyl, or C 3 -C 12 heterocycloalkyl, C 3 -C 12 heterocycloalkenyl, C 3 -C 12 heterocycloalkyl-C 1 -C 6 alkyl, C 3 -C 12 heterocycloalkenyl-C 1 -C 6 alkyl, C 4 -C 18 heteroaryl, C 5 -C 18 heteroalkyl, each of which is bonded via a C atom and has hetero atoms selected from the group of O, S and N;  
       R 5  is —CN or a —C(═O)—R 7  group;  
       R 6  independently has the same meanings as R 4  or is linear or branched C 1 -C 18 alkoxy, C 3 -C 12 cycloalkoxy, C 3 -C 12 cycloalkyl-C 1 -C 6 alkoxy, C 6 -C 18 aryloxy, C 7 -C 18 aralkyloxy, C 3 -C 12 heterocycloalkyloxy, C 3 -C 12 heterocycloalkyl-C 1 -C 6 alkyloxy, C 4 -C 18 heteroaryloxy, C 5 -C 18 heteroaralkyl having hetero atoms selected from the group of O, S and N;  
       R 7  is linear or branched C 1 -C 18 alkyl, C 2 -C 18 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkyl-C 1 -C 6 alkyl, C 3 -C 12 cycloalkenyl-C 1 -C 6 alkyl, C 6 -C 18 aryl, C 7 -C 18 aralkyl, or C 3 -C 12 heterocycloalkyl, C 3 -C 1   2 heterocycloalkenyl, C 3 -C 12 heterocycloalkyl-C 1 -C 6 alkyl, C 3 -C 12 heterocycloalkenyl-C 1 -C 6 alkyl, C 4 -C 18 heteroaryl, C 5 -C 18 heteroalkyl, each of which is bonded via a C atom and has hetero atoms selected from the group of O, S and N, linear or branched C 1 -C 18 alkoxy, C 3 -C 12 cycloalkoxy, C 3 -C 12 cycloalkyl-C 1 -C 6 alkoxy, C 6 -C 18 aryloxy, C 7 -C 18 aralkyloxy, C 3 -C 12 heterocycloalkyloxy, C 3 -C 12 heterocycloalkyl-C 1 -C 6 alkyloxy, C 4 -C 18 heteroaryloxy, C 5 -C 18 heteroaralkyl having hetero atoms selected from the group of O, S and N;  
       R 4  and R 6  together with the group —C—C(═O)— to which they are bonded are an aliphatic or heteroaromatic, saturated or unsaturated, single or polycyclic ring which contains 3 to 18 ring members and to which aromatic or heteroaromatic rings may be fused;  
       R 6  and R 7  together with the group —(O═)C—C—C(═O)— to which they are bonded are an aliphatic or heteroaromatic, saturated or unsaturated, single or polycyclic ring which contains 3 to 18 ring members and to which aromatic or heteroaromatic rings may be fused;  
       where R 4 , R 5 , R 6  and R 7  are unsubstituted or substituted as defined above for methylene and methine compounds.  
     
     
       4. The process according to  claim 1 , wherein the halogenation reagent is a fluorination reagent selected from the group of inert gas fluorides, fluoroalkoxyfluorides, sulfonyl fluorides, N-fluorinated pyridinium salts, tertiary N-fluoroammonium salts, N-fluorinated amides and imides, FClO 3 , and F 2 . 
     
     
       5. The process according to  claim 4 , wherein the fluorination reagent is selected from the group of xenon difluoride, (CF 3 ) 2 CFOF, CF 3 SO 2 F, N-fluorinated internal salts of pyridines and bipyridyls substituted by sulfo groups, triflates or tetrafluoroborates of N-fluorinated pyridines and bipyridyls, N-alkylated and N-fluorinated sulfonamides, carboxamides, lactams and sultams, N-fluorinated dicarboximides and disulfonimides. 
     
     
       6. The process according to  claim 4 , wherein the fluorination reagent is a 1-substituted 4-fluoro-1,4-diazoniabicyclo[2,2,2]octane salt with complex anions and substituents selected from C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl and C 1 -C 4 haloalkyl. 
     
     
       7. The process according to  claim 6 , wherein the fluorination reagent is 1-chloromethyl- or 1-hydroxymethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bistetraf luoroborate. 
     
     
       8. The process according to  claim 1 , wherein the halogenation reagent for the chlorination, bromination and iodination is selected from the group of C 1   2 , Br 2 , I 2 , N-chlorinated, N-brominated and N-iodinated dicarboximides or disulfonimides, lactams and sultams, N-alkyl- or N-phenylcarboxamides or -sulfonamides, dialkylamines or monoalkylamines. 
     
     
       9. The process according to  claim 8 , wherein the halogenation reagent is N-chloro-, N-bromo- or N-iodosuccinimide. 
     
     
       10. The process according to  claim 1 , wherein the titanium compounds of the formula I are titanium tetrachloride, titanium tetrabromide, cyclopentandienyltitanium trichloride and cyclopentadienyltitanium tribromide. 
     
     
       11. The process according to  claim 1 , wherein X 1  and X 2  in formula II are bromine or chlorine. 
     
     
       12. The process according to  claim 1 , wherein the diolates are divalent radicals of diols whose hydroxyl groups are bonded in the 1,3, 1,4 or 1,5 positions of a substituted or unsubstituted C 3 , C 4  or C 5  chain in an open-chain, cyclic or cyclic-aliphatic compound, and substituents selected from the group of halogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 4 alkyl, C 6 -C 10 aryl, C 7 -C 12 aralkyl, and, bonded in the 2 and/or 3 position, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, C 3 -C 8 cycloalkyl-C 1 -C 4 alkoxy, C 6 -C 10 aryloxy, C 7 -C 12 aralkyloxy, or, bonded in the 2,3 position and unsubstituted or substituted by a hydrocarbon radical as defined above, trimethylene, tetramethylene, ethylene-1,2-dioxy or methylenedioxy, where cyclic substituents in turn are unsubstituted or substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen. 
     
     
       13. The process according to  claim 12 , wherein the diolates are 1,4-diolates including 1,1′ bicyclic hydrocarbons with hydroxyl groups bonded in the 2,2′ position. 
     
     
       14. The process according to  claim 12 , wherein the butane-1,4-diolates have the formula VII                    
       in which 
       Y 3 , Y 4 , Y 5 , Y 6 , Y 7  and Y 8  are, independently of one another, a hydrogen atom, C 1 -C 8 alkyl and preferably C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl and preferably C 5 -C 6 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 4 alkyl and preferably C 5 -C 6 cycloalkylmethyl or -ethyl, C 6 -C 10 aryl and preferably phenyl or naphthyl, C 7 -C 12 aralkyl and preferably benzyl and phenylethyl;  
       Y 5  and Y 6  are C 1 -C 8 alkoxy and preferably C 1 -C 4 alkoxy, C 3 -C 8 cycloalkoxy and preferably C 5 -C 6 cycloalkoxy, C 3 -C 8 cycloalkyl-C 1 -C 4 alkoxy and preferably C 5 -C 6 cycloalkylmethoxy or -ethoxy, C 6 -C 10 aryloxy and preferably phenyloxy or naphthyloxy, C 7 -C 12 aralkyloxy and preferably benzyloxy and phenylethyloxy;  
       Y 5  and Y 6  are, together with the C atoms to which they are bonded, C 5 -C 8 cycloalkyl; or  
       Y 5  and Y 6  are together with the C atoms to which they are bonded, the radical —O—CY 9 Y 10 —O—;  
       Y 9  and Y 10  are, independently of one another, a hydrogen atom, C 1 -C 8 alkyl and preferably C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl and preferably C 5 -C 6 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 4 alkyl and preferably C 5 -C 6 cycloalkylmethyl or -ethyl, C 6 -C 10 aryl and preferably phenyl or naphthyl, C 7 -C 12 aralkyl and preferably benzyl and phenylethyl;  
       Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9  and Y 10  are unsubstituted or substituted by halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;  
       with the proviso that at least one of Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9  and Y 10  is one of said radicals.  
     
     
       15. The process according to  claim 14 , wherein Y 5  and Y 6  in formula VII are, together with the C atoms to which they are bonded, C 5 -C 8 cycloalkyl or the radical —O—CY 9 Y 10 —O—. 
     
     
       16. The process according to  claim 1 , which is enantioselective through use of compounds of the formula II in which R 2  and R 3  are an enantiopure 1,3-, 1,4- or 1,5-diolate as catalysts for reacting activated racemic methine compounds. 
     
     
       17. The process according to  claim 16 , wherein the enantiopure diolate has the formula VII according to  claim 14 , or the formulae V, VI                    
       in which Y 1  and Y 2  are C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen, and no or 5- or 6-membered carbocyclic rings are fused to the benzene rings, or have the formulae                    
     
     
       18. The process according to  claim 16 , wherein the enantiopure diolate is (4R,5R)- and (4S,5S)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane or (4R,5R)- and (4S,5S)-4,5-bis(di-1-naphthylhydroxymethyl)-2,2-dimethyidioxolane. 
     
     
       19. The process according to  claim 1 , wherein the catalyst is employed in an amount of 0.5 to 20 mol % based on the activated methylene or methine compounds. 
     
     
       20. The process according to  claim 1 , which is carried out at a temperature of from −40 to 120° C. 
     
     
       21. The process according to  claim 13 , wherein the 1,4-diolate is a 1,1′ bicyclic hydrocarbon with hydroxyl groups bonded in the 2,2′ positions. 
     
     
       22. The process according to  claim 14 , wherein Y 3 , Y 4 , Y 5 , Y 6 , Y 7  and Y 8  are, independently of one another, C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkylmethyl or -ethyl, phenyl, napthyl, benzyl or phenylethyl; 
       Y 5  and Y 6  are C 1 -C 4 alkoxy, C 5 -C 6 cycloalkoxy, C 5 -C 6 cycloalkylmethoxy or -ethoxy, phenyloxy, napthyloxy, benzyloxy or phenylethloxy;  
       Y 9  and Y 10  are, independently of one another, C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkylmethyl or -ethyl, phenyl, naphthyl, benzyl or phenylethyl.  
     
     
       23. The process according to  claim 17 , wherein Y 3 , Y 4 , Y 5 , Y 6 , Y 7  and Y 8  are, independently of one another, C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkylmethyl or -ethyl, phenyl, napthyl, benzyl or phenylethyl; 
       Y 5  and Y 6  are C 1 -C 4 alkoxy, C 5 -C 6 cycloalkoxy, C 5 -C 6 cycloalkylmethoxy or -ethoxy, phenyloxy, napthyloxy, benzyloxy or phenylethloxy;  
       Y 9  and Y 10  are, independently of one another, C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkylmethyl or -ethyl, phenyl, naphthyl, benzyl or phenylethyl.